Predictive Factors Associated With Acute Ocular
Involvement in Stevens-Johnson Syndrome and
Toxic Epidermal Necrolysis
CHIE SOTOZONO, MAYUMI UETA, EIJI NAKATANI, AMANE KITAMI, HIDEAKI WATANABE,
HIROHIKO SUEKI, MASAFUMI IIJIMA, MICHIKO AIHARA, ZENRO IKEZAWA, YUKOH AIHARA, YOKO KANO,
TETSUO SHIOHARA, MIKIKO TOHYAMA, YUJI SHIRAKATA, HIDEAKI KANEDA, MASANORI FUKUSHIMA,
SHIGERU KINOSHITA, AND KOJI HASHIMOTO, ON BEHALF OF THE JAPANESE RESEARCH COMMITTEE ON
SEVERE CUTANEOUS ADVERSE REACTION

PURPOSE: To suggest an objective score for grading the
acute ocular severity of Stevens-Johnson syndrome (SJS)
and toxic epidermal necrolysis (TEN), and to determine
predictive factors for severe acute ocular involvement
such as ocular surface epithelial defect and/or pseudo-
membrane formation.

DESIGN: Retrospective cohort study.

METHODS: The medical records of SJS (n [ 87) and
TEN (n [ 48) patients between 2005 and 2007 were
reviewed. An acute ocular severity score was determined
on a scale from 0 to 3 (none, mild, severe, and very se-
vere) according to the existence of hyperemia, corneal
or conjunctival epithelial defect, and pseudomembrane
formation. The associations between the severe acute
ocular involvement and factors such as patient age,
exposed drugs, systemic severity, and the prevalence of
ocular sequelae were examined.

RESULTS: The number of cases with score grade 0, 1, 2,
and 3 was 19 (21.8%), 31 (35.6%), 22 (25.3%), and 15
(17.2%) in 87 SJS cases and 12 (25.0%), 11 (22.9%),
17 (35.4%), and 8 (16.7%) in 48 TEN cases. Multivariate
logistic regression analysis revealed that patient age (odds
ratio [OR], 0.98; 95% confidence interval [CI], 0.96
0.99; P [ .007) and nonsteroidal anti-inflammatory drugs
NSAIDs or cold remedies (OR, 2.58; 95% CI, 1.265.29;
P [ .010) were predictive factors for severe acute ocular
Supplemental Material available at AJO.com.
Accepted for publication May 4, 2015.
From the Department of Ophthalmology, Kyoto Prefectural University
of Medicine, Kyoto, Japan (C.S., M.U., S.K.); the Department of
Dermatology, Showa University School of Medicine, Tokyo, Japan
(A.K., H.W., H.S., M.I.); the Department of Dermatology, Yokohama
City University Medical Center, Yokohama, Japan (M.A., Z.I.); the
Department of Pediatrics, Yokohama City University Medical Center,
Yokohama, Japan (Y.A.), the Department of Dermatology, Kyorin
University School of Medicine, Tokyo, Japan (Y.K., T.S.); the
Department of Dermatology, Ehime University Graduate School of
Medicine, Matsuyama, Japan (M.T., Y.S., K.H.); and the Translational
Research Informatics Center, Foundation for Biomedical Research and
Innovation, Kobe, Japan (E.N., H.K., M.F.).
Inquiries to Chie Sotozono, Department of Ophthalmology, Kyoto
Prefectural University of Medicine, 465 Kajii-cho, Hirokoji-agaru,
Kawaramachi-dori, Kamigyo-ku, Kyoto 602-0841, Japan; e-mail:
csotozon@koto.kpu-m.ac.jp
228 2015 BY ELSEVIER INC. ALL
involvement. The prevalence of visual disturbance and eye
dryness increased according to the increase of acute ocular
severity (P [ .001 and P [ .007 in SJS; P [ .007 and
P [ .014 in TEN, respectively).

CONCLUSIONS: At the onset of SJS/TEN, strict attention
should be paid to ocular involvement in young patients and in
patients exposed to NSAIDs or cold remedies. (Am J
Ophthalmol 2015;160(2):228237. 2015 by Elsevier
Inc. All rights reserved.)
S
TEVENS-JOHNSON SYNDROME (SJS) AND ITS MORE
severe variant, toxic epidermal necrolysis (TEN),
are acute inflammatory disorders of the skin and mu-
cous membranes that predispose patients to life-
threatening complications such as sepsis, respiratory
dysfunction, and multiple organ failure.14 Both diseases
are rare, yet can affect anyone, regardless of age, and
usually as a consequence of adverse drug reactions. A
variety of drugs including antibiotics, nonsteroidal anti-
inflammatory drugs (NSAIDs), and antiepileptic medica-
tions (ie, many if not most of the popularly used over-
the-counter drugs) have been reported to cause severe
drug reactions and induce SJS or TEN.5,6 Ocular surface
inflammation develops rapidly at the acute stage of the
disease, and acute conjunctivitis occur prior to, or
simultaneously with, skin eruptions.7 Extensive inflamma-
tion of the ocular surface is often accompanied by corneal
and/or conjunctival epithelial defects. Common signs after
the acute stage include persistent epithelial defects, ulcer-
ation, and perforation, ultimately developing into corneal,
conjunctival, and eyelid cicatricial changes such as neovas-
cularization, opacification, keratinization, and symble-
pharon.7,8 Visual impairment and severe dryness of the
eye continue lifelong as ocular sequelae.7,8 Although we
previously reported both surgical914 and nonsurgical15
therapeutic methods to treat chronic-stage SJS/TEN, it re-
mains impossible to restore the ocular surface to its normal
healthy state (ie, that of before disease onset).
In a previous report from Power and associates,16 the au-
thors categorized acute ocular severity into the grades of
mild, severe, or very severe. In that grading system, mild
RIGHTS RESERVED. 0002-9394/$36.00
http://dx.doi.org/10.1016/j.ajo.2015.05.002
involvement was defined as mild conjunctival injection, lid
edema, and/or chemosis; moderate involvement consisted of TABLE 1. Diagnostic Criteria for Stevens-Johnson
membrane formation, corneal epithelial loss of more than Syndrome and Toxic Epidermal Necrolysis by Japanese
Ministry of Health, Labour and Welfare (2005)
30%, corneal ulceration, and/or corneal infiltrates; and se-
vere involvement consisted of fornix shortening, symble- Diagnostic Criteria
pharon formation, and/or visual loss. Considering the fact
that SJS and TEN are characterized by epidermal necrosis Stevens-Johnson
syndrome
with detachment and erosion of the mucous membranes,2,17
Clinical entity A severe mucocutaneous disorder
corneal or conjunctival epithelial defects are prominent
characterized by erythema, epidermal
disease-related factors at the onset. In addition, it is reported detachment, and enanthema
that extreme inflammation develops on the ocular surface accompanied by high fever
accompanying pseudomembrane formation at the acute Essential criteria 1. Severe hyperemic and/or hemorrhagic
stage.16,18,19 Thus, we hypothesized that a simple grading (required) mucocutaneous lesions
system based on the presence of conjunctivitis, corneal or 2. Epidermal detachment involving <10%
conjunctival epithelial defect, and pseudomembrane of the total body surface area
formation might be appropriate to evaluate acute ocular 3. High-grade fever (> _38.0 8 C) in the
severity of SJS/TEN. absence of antipyretic therapy
Owing to the high mortality rate of patients with SJS and Supportive 1. Flat, atypical target lesions
findings 2. Bilateral acute keratoconjunctivitis
TEN (1%w5% and 20%w30%, respectively), investiga-
accompanied by ocular surface epithelial
tions of these diseases have been intensively focused on sys-
defect and/or pseudomembrane
temic severity and general treatment.6,2022 Unfortunately, formation
even in the large-scale survey of the severe adverse drug re- 3. Histologic evidence of epidermal
actions conducted in Europe,4,2123 the ocular involvement necrosis
was not explored. Moreover, the predictive features of Toxic epidermal
ocular involvement at the acute stage of SJS/TEN remain necrolysis
unclear. Clinical entity A severe mucocutaneous disorder
The aim of this study was to construct a simpler and more characterized by extensive erythema,
practical score for grading the acute ocular severity of SJS epidermal detachment (including blisters
and TEN, as well as to determine predictive factors having and erosions), and enanthema
accompanied by high fever. The extent of
severe or very severe (as opposed to none or mild) acute
epidermal detachment is > _10% of the
ocular involvement in SJS/TEN patients based on a Japa-
total body surface area
nese nationwide retrospective study of SJS and TEN patients Essential criteria 1. Epidermal detachment involving >10%
in which both dermatologists and ophthalmologists partici- (required) of the total body surface area
pated.24 Furthermore, correlation between the severe acute 2. Exclusion of staphylococcal scalded skin
ocular involvement and the prevalence of ocular sequelae syndrome
(visual disturbance and dryness of the eye) was examined. 3. High-grade fever (> _38.0 8 C) in the
absence of antipyretic therapy
Supportive 1. Generalized macular or diffuse erythema
findings 2. Enanthema including bilateral acute
keratoconjunctivitis accompanied by
METHODS ocular surface epithelial defect and/or
pseudomembrane formation
THIS STUDY WAS APPROVED BY THE ETHICS COMMITTEE
3. Histologic evidence of marked epidermal
and Institutional Review Board of Kyoto Prefectural Uni- necrosis
versity of Medicine, Kyoto, Japan (RBMR-E-215), and
was carried out in accordance with the tenets set forth in
the Declaration of Helsinki.
institutions, and dermatologists from 212 medical institu-

PATIENTS: In order to investigate ocular involvement in tions responded. Secondly, case report forms (CRFs) were
SJS/TEN patients as a first step, we retrospectively sent to dermatologists. Based on the medical records in
reviewed SJS and TEN patients who were diagnosed in each institution, patients matching the diagnostic criteria
the period from January 2005 to December 2007, with for SJS and TEN, which was made by the Japanese Ministry
the medical records of those patients being obtained from of Health, Labour and Welfare in 2005 (Table 1) (diagnostic
dermatologists.24 criteria and systemic severity index score for Stevens-
Johnson syndrome available at http://www.nanbyou.or.jp/

DATA COLLECTION: To identify SJS and TEN patients, a entry/3680, accessed April 21, 2015), were determined.
questionnaire was first sent to dermatologists at 607 medical The CRF was structured as follows: (1) diagnostic criteria,

VOL. 160, NO. 2 SIMPLE SCORING OF OCULAR SEVERITY AND PREDICTIVE FACTORS IN SJS/TEN 229
(2) patient information (ie, sex, age, past medical history
and accompanying systemic diseases), (3) exposed drugs,
(4) clinical symptoms, (5) systemic findings (ie, existence
of a high fever and/or respiratory problem, the quality and
location of a rash, and involvement of the lips, mouth, or
other mucous membrane), (6) laboratory findings, and (7)
a histopathologic examination of a skin biopsy. The results
by this study for systemic and dermatologic findings had
already been reported.24
Then, for registration of this survey, CRFs for investi-
gating ocular involvement were sent to ophthalmologists,
to whom patients were referred by dermatologists, and
the patients who were treated by ophthalmologists were
selected as this study population. This ophthalmologic
CRF consisted of (1) ocular surface findings at first appear-
ance, at the day of worst severity, and at last appearance,
with the sketches of epithelial defect and pseudomembrane
formation being included; (2) pre-existing ocular diseases;
(3) ocular sequelae at the chronic stage (ie, visual distur-
bance and eye dryness); and (4) exposed drug and therapeu-
tic drugs. Ocular surface findings at the acute stage were
graded as an acute ocular severity score, as described below
(Table 2). Ocular findings at last appearance (at the
chronic stage) were graded as per the previously described
methods.8 Exposed drugs were categorized to NSAIDs, cold
remedies, antibiotics, anticonvulsants, and others. The re-
cords of steroid pulse therapy, high-dose steroids, intrave-
nous immunoglobulin, plasmapheresis as systemic
therapy, and topical antibiotics and steroids were collected.

ACUTE OCULAR SEVERITY SCORE, DEFINITION AND
MEASUREMENT: In this study, ocular surface findings at
the acute stage were graded as an acute ocular severity score
ranging from grade 0 to 3, which were termed as none,
mild, severe, and very severe (Table 2). We consid- logistic regression model was used to determine predictive
ered that ocular surface inflammation and epithelial necro-
sis or apoptosis might be the initial ocular pathologic
processes of SJS/TEN. Conjunctival hyperemia, which in-
dicates ocular surface inflammation, was assessed as grade 1.
Eyes with accompanying pseudomembrane formation or
ocular surface epithelial defect were assessed as grade 2.
Eyes with both pseudomembrane formation and ocular sur-
face epithelial defect were assessed as grade 3. In addition,
we checked all of the sketches of ocular surface appearances
contained within the ophthalmologic CRF.
The acute stage was defined as the first 2 months from
onset, because both SJS and TEN are self-limited until
68 weeks after onset. In addition, the acute ocular severity
scores at the day of worst severity during the acute stage
were documented, because ocular severity at the acute
stage often worsens, even during medical treatment.16,18
In cases where the acute ocular severity differed between
both eyes, the more severe eye was chosen as the eye to
be evaluated.
The systemic severity index score is a summed score,
shown in the Supplemental Table (available at AJO.com),
230 AMERICAN JOURNAL OF OPHTHALMOLOGY
TABLE 2. Grading Scores for Acute Ocular Severity of
Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
Acute Ocular Manifestations Grade
No ocular involvement 0 (none)
Conjunctival hyperemia 1 (mild)
Either ocular surface epithelial defect or 2 (severe)
pseudomembrane formation
Both ocular surface epithelial defect and 3 (very severe)
pseudomembrane formation
with the maximum score being 14. Moreover, the systemic
severity index subscore is defined as a summed score that in-
cludes the score for surface area of skin lesions on the body,
except for the score for ocular lesion, with the maximum
score being 11.

STATISTICAL ANALYSIS: Acute ocular severity at the
day of worst severity was compared to various factors
such as the patients age, sex, exposed drugs, and the sys-
temic severity index subscore (Supplemental Table). In
addition, predictive factors at diagnosis associated with
acute ocular severity were examined. Finally, correlation
between the acute ocular severity score and the prevalence
of ocular sequelae (visual disturbance and eye dryness) was
examined.
To summarize the data, the mean (standard deviation
[SD]) for continuous variables and frequencies (%) for cat-
egorical variables were used. To examine whether or not
the increase of acute ocular severity affected the linear
trend for each factor, the Jonckheere-Terpstra test of trend
for continuous variables and the Cochran-Armitage test of
trend for categorical variables were used. In addition, the
factors for categories of the acute ocular severity score,
which included the cases with no or mild ocular involve-
ment (acute ocular severity score grades 0 and 1, as refer-
ence) and the cases with severe or very severe ocular
involvement (acute ocular severity score grades 2 and 3).
The candidate predictive factors were selected with a P
value of <.05 for the Wald test in univariate analysis,
and the predictive factors were selected from those factors
by using the reverse method with a P value of <.05 for each
factor in multivariate analysis. The odds ratios (ORs) and
the corresponding 95% confidence intervals (CIs) based
on the Wald test were then estimated. All analyses were
performed by SAS version 9.3 (SAS Institute, Cary, North
Carolina, USA).
RESULTS

PATIENT CHARACTERISTICS AND THERAPY: In the
current study, 87 SJS patients and 48 TEN patients were
AUGUST 2015
 TABLE 3. Relationship Between Factors and Acute Ocular Severity Score in the Patients With Stevens-Johnson Syndrome and Toxic
Epidermal Necrolysis

Acute Ocular Severity Score

Variable 0 (None) 1 (Mild) 2 (Severe) 3 (Very Severe) P Value

Stevens-Johnson syndrome (N 87) N 19 N 31 N 22 N 15

Demographic variables
Sex, n (%)
Male 7 (36.8%) 16 (51.6%) 8 (36.4%) 5 (33.3%) .567
Age at onset
Mean 6 SD, y 57.1 6 18.2 52.3 6 18.7 54.4 6 19.1 39.2 6 19.2 .050
<50, n (%) 7 (36.8%) 11 (35.5%) 8 (36.4%) 11 (73.3%) .054
Systemic severity index subscore
Mean 6 SD 4.5 6 1.6 3.9 6 1.8 4.0 6 1.6 4.8 6 1.4 .579
Median (range) 5.0 (17) 4.0 (18) 4.0 (17) 5.0 (27)
Exposed drug, n (%)
NSAIDs
Yes 9 (47.4%) 10 (32.3%) 9 (40.9%) 9 (60.0%) .394
Cold remedies
Yes 1 (5.3%) 3 (9.7%) 3 (13.6%) 4 (26.7%) .062
Antibiotics
Yes 4 (21.1%) 6 (19.4%) 3 (13.6%) 1 (6.7%) .212
Anticonvulsants
Yes 4 (21.1%) 14 (45.2%) 6 (27.3%) 2 (13.3%) .370
Toxic epidermal necrolysis (N 48) N 12 N 11 N 17 N8
Demographic variables
Sex, n (%)
Male 5 (41.7%) 6 (54.5%) 8 (47.1%) 4 (50.0%) .794
Age at onset
Mean 6 SD, y 62.0 6 14.5 64.6 6 25.5 47.9 6 19.0 39.6 6 14.6 .062
<50, n (%) 2 (16.7%) 2 (18.2%) 9 (52.9%) 6 (75.0%) .002
Systemic severity index subscore
Mean 6 SD 7.1 6 1.7 8.3 6 2.2 8.0 6 1.5 8.0 61.3 .335
Median (range) 7.5 (49) 9.0 (311) 9.0 (410) 8.5 (69)
Exposed drug, n (%)
NSAIDs
Yes 3 (25.0%) 2 (18.2%) 9 (52.9%) 4 (50.0%) .079
Cold remedies
Yes 0 (0.0%) 0 (0.0%) 6 (35.3%) 2 (25.0%) .015
Antibiotics
Yes 0 (0.0%) 5 (45.5%) 4 (23.5%) 1 (12.5%) .578
Anticonvulsants
Yes 2 (16.7%) 1 (9.1%) 4 (23.5%) 2 (25.0%) .463

NSAIDs nonsteroidal anti-inflammatory drugs.

The Jonckheere-Terpstra test of trend for continuous variables and the Cochran-Armitage test of trend for categorical variables
were used.

identified from institutions throughout Japan. Of those pa-
tients, 36 SJS patients (41.4%) and 23 TEN patients
(47.9%) were men. In addition, the mean age (SD) for
SJS and TEN patients was 51.6 (19.4) and 53.9 (20.8),
respectively. Systemic steroid pulse therapy was adminis-
tered in 40 SJS cases (46.0%) and in 28 TEN cases
(58.3%). Intravenous immunoglobulin was administered
in 8 SJS cases (9.2%) and in 21 TEN cases (43.3%). Plas-
mapheresis was performed in 3 SJS cases (3.4%) and in
10 TEN cases (20.8%). Of the 104 cases with ocular
involvement, antibiotics and steroids were administered
in 74 cases (71.2%) and 85 cases (81.7%), respectively.
Topical steroids were administered in all 23 cases with
acute ocular severity score grade 3 (very severe).

ACUTE OCULAR SEVERITY SCORE: Of the 87 SJS cases,
the acute ocular severity score was grade 0 in 19 cases
(21.8%), grade 1 in 31 cases (35.6%), grade 2 in 22 cases

VOL. 160, NO. 2 SIMPLE SCORING OF OCULAR SEVERITY AND PREDICTIVE FACTORS IN SJS/TEN 231
FIGURE 1. Representative slit-lamp appearances of Stevens-Johnson syndrome (SJS)- and toxic epidermal necrolysis (TEN)-
associated ocular involvement at the acute stage. Bilateral conjunctivitis with hyperemia (Top left) is the most frequently associated
ocular finding. Pseudomembrane formation (Top right) is seen in cases accompanying extensive ocular surface inflammation. Ocular
surface corneal (Middle left) or conjunctival (Bottom left) epithelial defects can easily be seen by fluorescein staining (Middle right
and Bottom right).

(25.3%), and grade 3 in 15 cases (17.2%) (Table 3). Of the
48 TEN cases, the score was grade 0 in 12 cases (25.0%),
grade 1 in 11 cases (22.9%), grade 2 in 17 cases (35.4%),
and grade 3 in 8 cases (16.7%) (Table 3). The typical find-
ings observed in such cases are shown in Figure 1.

ASSOCIATION BETWEEN CHARACTERISTICS AT
DIAGNOSIS AND ACUTE OCULAR SEVERITY SCORE: The
acute ocular severity scores in male subjects were similar to
those in female subjects in both SJS (P .603) and TEN
(P .940). Patient age at disease onset tended to be younger
in the group with severe or very severe ocular involvement
than in the group with no or mild ocular involvement in
both disease categories (SJS: P .050; TEN: P .062)
(Figure 2 and Table 3). In addition, the systemic severity
index subscores did not differ among the 4 groups according
to the acute ocular severity score in both SJS and TEN (SJS:
P .579; TEN: P .335) (Table 3).
NSAIDs were the exposed drugs in more than 40.0% of
the SJS and TEN cases with an acute ocular severity score
grade 2 and 3; however, the use of NSAIDs was found to
not be associated with the acute ocular severity (SJS:
P .394; TEN: P .079) (Table 3). In addition, the
use of cold remedies (as the exposed drugs) was found to
be increased according to the worsening of acute ocular
severity in TEN patients (P .015), but not in SJS pa-
tients (P .062) (Table 3). The use of antibiotics was
found to not be associated with the acute ocular severity
(SJS: P .212; TEN: P .578) (Table 3). Furthermore,
the use of anticonvulsants was found to not be associated

232 AMERICAN JOURNAL OF OPHTHALMOLOGY AUGUST 2015

FIGURE 2. Relationship between the acute ocular severity score and patient age in the Stevens-Johnson syndrome (SJS) and toxic
epidermal necrolysis (TEN) cases. The horizontal line within each shaded box represents the median value, and the bottom and top
lines of each box represent the 25th and 75th percentiles, respectively. The vertical lines extending from the top and bottom of each
box represent the lowest and highest values, respectively (or are located 1.5 times the interquartile range away from the box). The
Jonckheere-Terpstra test was used to determine whether or not patient age was related to the severity scores.

TABLE 4. Logistic Regression Analysis of the Association Between Variables at Onset and Acute Ocular Severity in Patients With
Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

Univariate Logistic Regression Multivariate Logistic Regression

Variable at Onset N 135 OR 95% CI P Value OR 95% CI P Value

Disease: TEN (vs SJS) 1.47 0.722.98 .287

Sex: male (vs female) 0.78 0.391.54 .466
Age at onset (y) 0.97 0.960.99 .004 0.98 0.960.99 .007
_)
Age at onset (y): >50 (vs 50< 0.36 0.180.72 .004
NSAIDs 2.04 1.024.1 .045
Cold remedies 5.51 1.7217.62 .004
NSAIDs or cold remedies 2.68 1.335.38 .006 2.58 1.265.29 .010
Antibiotics 0.66 0.271.63 .363
Anticonvulsants 0.72 0.331.58 .415

CI confidence interval; NSAIDs nonsteroidal anti-inflammatory drugs; OR odds ratio; SJS Stevens-Johnson syndrome; TEN toxic
epidermal necrolysis.

with the acute ocular severity (SJS: P .370; TEN: P
.463) (Table 3).

PREDICTIVE FACTORS AT DIAGNOSIS ASSOCIATED
WITH ACUTE OCULAR SEVERITY: A total of 135 patients
were analyzed. Univariate logistic regression analysis
revealed that disease (TEN or SJS) was not associated
with acute ocular severity (grade 2 and 3 vs grade 0 and
1, OR: 1.47, 95% CI: 0.722.98, P .287). In contrast, pa-
tient age (OR: 0.97, 95% CI: 0.960.99, P .004) and
NSAIDs (OR: 2.04, 95% CI: 1.024.10, P .045), cold
remedies (OR: 5.51, 95% CI: 1.7217.6, P .004), and
NSAIDs or cold remedies (OR: 2.68, 95% CI: 1.335.38,
P .006) were associated with acute ocular severity (grade
2 and 3 vs grade 0 and 1) as the candidate predictive factors
(Table 4). Further, in multivariate logistic regression anal-
ysis, patient age (OR: 0.98, 95% CI: 0.960.99, P .007)
and NSAIDs or cold remedies (OR: 2.58, 95% CI: 1.26
5.29, P .010) were identified as predictive factors for
acute ocular severity (grade 2 and 3 vs grade 0 and 1).

CORRELATION BETWEEN ACUTE OCULAR SEVERITY
SCORE AND PREVALENCE OF OCULAR SEQUELAE: As
ocular sequelae, visual disturbance (defined as best-
corrected visual acuity [BCVA] worse than 20/20) was
observed in 15 SJS patients (15/87, 17.2%) and in 6 TEN
patients (6/48, 12.5%) (Table 5). In both SJS and TEN,
the prevalence of visual disturbance (BCVA worse than

VOL. 160, NO. 2 SIMPLE SCORING OF OCULAR SEVERITY AND PREDICTIVE FACTORS IN SJS/TEN 233
 TABLE 5. Prevalence of Ocular Sequelae Stratified by Acute Ocular Severity Score in Patients With Stevens-Johnson Syndrome and
Toxic Epidermal Necrolysis

Acute Ocular Severity Score

Variable Category 0 (None) 1 (Mild) 2 (Severe) 3 (Very Severe) P Valuea

Stevens-Johnson syndrome N 19 N 31 N 22 N 15
Visual disturbance Better than 20/20 of BCVA 18 (94.7%) 29 (93.5%) 16 (72.7%) 9 (60.0%) .001
20/20 - 20/200 of BCVA 1 (5.3%) 1 (3.2%) 6 (27.3%) 5 (33.3%)
Worse than 20/200 of BCVA 0 (0.0%) 1 (3.2%) 0 (0.0%) 1 (6.7%)
Severity of dry eye None 17 (89.5%) 24 (77.4%) 11 (50.0%) 7 (46.7%) .001
Mild 2 (10.5%) 6 (19.4%) 6 (27.3%) 6 (40.0%)
Moderate 0 (0.0%) 1 (3.2%) 4 (18.2%) 1 (6.7%)
Severe 0 (0.0%) 0 (0.0%) 1 (4.5%) 1 (6.7%)
Toxic epidermal necrolysis N 12 N 11 N 17 N8
Visual disturbance Better than 20/20 of BCVA 12 (100.0%) 11 (100.0%) 14 (82.4%) 5 (62.5%) .007
20/20 - 20/200 of BCVA 0 (0.0%) 0 (0.0%) 2 (11.8%) 3 (37.5%)
Worse than 20/200 of BCVA 0 (0.0%) 0 (0.0%) 1 (5.9%) 0 (0.0%)
Severity of dry eye None 11 (91.7%) 6 (54.5%) 9 (52.9%) 3 (37.5%) .014
Mild 1 (8.3%) 4 (36.4%) 7 (41.2%) 3 (37.5%)
Moderate 0 (0.0%) 1 (9.1%) 0 (0.0%) 2 (25.0%)
Severe 0 (0.0%) 0 (0.0%) 1 (5.9%) 0 (0.0%)

BCVA best-corrected visual acuity.

a
P values of Cochran-Armitage trend test were calculated by 2 categories of better or worse than 20/200 of BCVA in visual disturbance and 2
categories of none or more than mild severity of dry eye.

20/20) increased according to the increase of acute ocular
severity (SJS: P .001; TEN: P .007) (Figure 3 and
Table 5). In addition, dry eye (as ocular sequelae) was
observed in 28 of 87 SJS patients (32.2%) and in 18 of
48 TEN patients (37.5%) (Table 5). Furthermore, in
both SJS and TEN, the prevalence of more than mild dry
eye increased according to the increase of acute ocular
severity (SJS: P .001; TEN: P .014) (Figure 3 and
Table 5).
DISCUSSION
SJS AND TEN ARE RARE, YET POTENTIALLY FATAL, SEVERE
skin mucosal disorders. Owing to the serious general symp-
toms and high mortality rates associated with these dis-
eases, the ocular involvement is often easily overlooked.
In addition, owing to the low incidence of acute SJS/
TEN, most ophthalmologists are unfamiliar with the find-
ings of acute ocular involvement. However, SJS/TEN pa-
tients with ocular sequelae (which can be associated with
acute ocular severity) need ophthalmic treatment for an
extended period of time and the quality of life of these pa-
tients is extremely poor.25,26 Furthermore, the findings of
this current study show that the chronic ocular sequelae
more frequently occurred in patients with severe or very
severe ocular involvement (grades 2 and 3 of the acute
ocular severity score) than in patients with no or mild
ocular involvement. Thus, strict attention must be paid
to ocular involvement at the acute stage.
On the other hand, the diagnostic criteria for SJS and
TEN produced by the Japanese Ministry of Health, Labour
and Welfare (2005) (Table 1) were determined by a
research group consisting of dermatologists and ophthal-
mologists who specialize in severe adverse drug reactions.
In these diagnostic criteria, the acute ocular severity was
included as accompanying findings. The systemic severity
index score, which is often referred to by dermatologists,
also includes the ocular surface findings as accompanied
findings (Supplemental Table, available at AJO.com).
Recognition of the acute ocular severity (and the corre-
sponding proper treatment) can work not only to reduce
the rate of ocular sequelae but also to produce an adequate
differential diagnosis.27 We believe that all dermatologists,
as well as all physicians who are not ophthalmologists,
should pay strict attention to ocular findings at disease
onset in SJS/TEN cases. Hence, from the aspect of the judg-
ment of acute ocular severity in SJS/TEN cases, this current
study provided a common platform.
The proposed acute ocular severity score included only
the initial ocular pathologic process. To the best of our
knowledge, at the onset of both SJS and TEN, it is vital
to elucidate the distinctive appearances of corneal and/or
conjunctival epithelial defects and pseudomembrane for-
mation. These ocular surface inflammation and epithelial
necrosis or apoptosis are part of the initial ocular pathologic
processes of SJS/TEN, and the secondary processes include

234 AMERICAN JOURNAL OF OPHTHALMOLOGY AUGUST 2015

FIGURE 3. Relationship between the acute ocular severity score and ocular sequelae in Stevens-Johnson syndrome (SJS) and toxic
epidermal necrolysis (TEN). The percentage rate of the presence of visual disturbance (Top 2 charts) and eye dryness (Bottom 2
charts) in the SJS and TEN cases, respectively, compared to the acute ocular severity score. The Cochran-Armitage test was used
to determine whether or not acute ocular severity was related to ocular sequelae.

persistent epithelial defects, ulceration and perforation,
fornix shortening, symblepharon formation, and vision
loss. Although the previously reported grading system
included the secondary ocular findings,16,28 our suggested
acute ocular severity scoring system included only the
initial ocular pathologic process to find the early
progression of ocular involvement.
We previously reported in a retrospective analysis that
visual prognoses were significantly better in the group
receiving topical steroids at the acute stage compared
with the no-treatment group.7 Based on our prospective
study, we have shown the therapeutic importance of a
corticosteroid pulse therapy and topical administration of
betamethasone at disease onset for reducing the degree of
ocular sequelae.18 At disease onset, a severe cytokine storm
arises on the ocular surface and was found to be related to
ocular severity.19 Thereby, we believe that prompt diag-
nosis of ocular involvement and early intervention by oph-
thalmologists might improve the patients visual prognosis.
The findings of this present study clearly demonstrated
that patient age is closely related to acute ocular severity.
Previous reports from ophthalmologists have described
the mean age of SJS/TEN patients as being around 25
years.7,8 On the other hand, the mean patient age
reported from dermatologists is around 45 years.6 Along
with those findings from the previous reports, our results
suggest that susceptibility to SJS/TEN with ocular involve-
ment differs depending on the patients age.
The findings of this study demonstrated that NSAIDs or
cold remedies as the exposed drugs are predictive factors for
the increase of acute ocular severity. In addition, those
drugs can be associated with the prevalence of ocular
sequelae, since acute ocular severity was found to be associ-
ated with ocular sequelae in this study. In SJS/TEN with
ocular sequelae, common flu symptoms (general malaise,
fever, sore throat, etc) reportedly precede skin eruptions
in 80% of the cases.7 Following the ingestion of cold med-
icine for such prodromal symptoms, skin eruptions, high fe-
ver, and bilateral conjunctivitis occurred with extreme
inflammation on the ocular surface. Hence, the ocular
symptoms of SJS/TEN can be assumed to be a drug-
induced inflammatory disorder.
The findings of our recent reports have elucidated the
participation of a genetic involvement in SJS/TEN.2941
In one report, we showed that a strong association exists
between HLA-A*02:06 and SJS/TEN with severe ocular
complication.31 SJS/TEN with severe ocular complication
signifies the cases with acute ocular severity score graded 2

VOL. 160, NO. 2 SIMPLE SCORING OF OCULAR SEVERITY AND PREDICTIVE FACTORS IN SJS/TEN 235
and 3 at the acute stage or the cases with severe ocular
sequelae at the chronic stage. In addition, we also clarified
that HLA-A*02:06 and HLA-B*44:03 are susceptible al-
leles that increase the risk of cold medicinerelated SJS/
TEN with severe ocular complication.41 This present study
clearly demonstrated the strong relations between NSAIDs
or cold remedies and SJS/TEN with severe ocular involve-
ment (grades 2 and 3). Most cold remedies include acet-
aminophen or NSAIDs such as aspirin, ibuprofen, or
others. Reportedly, there are statistically significant differ-
ences in the single nucleotide polymorphisms of toll-like
receptor 3 (TLR3),30 a pattern-recognizing receptor related
to innate immunity following viral infections. Polymor-
phisms of EP3, one of the prostaglandin E2 (PGE2) recep-
tors, are reportedly strongly associated with SJS/TEN with
severe ocular complication.36 Cold medicines and
NSAIDs, including ibuprofen and loxoprofen, commonly
downregulate the production of prostanoids, including
PGE2. Thus, we believe that interactions between HLA
risk factors, TLR3, and/or EP3 might be keys in the patho-
genesis of cold medicinerelated SJS/TEN with severe
ocular complication.34,37
It should be noted that this present study did have some
limitations, such as the sample size being too small to
perform statistical validation analysis for the simple scoring
of acute ocular severity. Thus, we were not able to analyze
the relations of the treatment.
In conclusion, we proposed simple criteria of acute
ocular involvement in patients with SJS and TEN, and
demonstrated that acute ocular severity was significantly
associated with patient age and exposed drugs. Further
studies are needed to validate our findings, yet based on
the identification of predictive factors associated with
ocular severity at the acute stage SJS/TEN, we emphasize
that strict attention must be paid to younger-age patients
and patients exposed to NSAIDs or cold remedies.

ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST.
Financial Disclosure(s): The authors have no conflicts of interest to disclose. Funding/Support: Supported in part by a Grant-in-Aid for Scientific Research
from the Japanese Ministry of Health, Labor and Welfare, and a Research Grant from the Japanese Ministry of Education, Culture, Sports, Science and
Technology. All authors attest that they meet the current ICMJE requirements to qualify as authors.
The authors wish to thank for Ms Saeko Miyazaki (Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan) of Kyoto
Prefectural University of Medicine for help with data collection; Ms Naoko Kashiwagi for her support of study management; Ms Satomi Sakabayashi, Ms
Kotone Matsuyama, and Dr Yoshihiro Matsubara for their support of statistical analysis; and Mr John Bush (Department of Ophthalmology, Kyoto Pre-
fectural University of Medicine, Kyoto, Japan) for proofreading the manuscript.
Collaborators: The Japanese Research Committee on Severe Cutaneous Adverse Reaction Group: Keisuke Nagao (Department of Dermatology, Keio
University, Tokyo, Japan), Eishin Morita (Department of Dermatology, Shimane University, Shimane, Japan), Kenji Kabashima (Department of Derma-
tology, Kyoto University Graduate School of Medicine, Kyoto, Japan), Hiroaki Azukizawa (Department of Dermatology, Osaka University Graduate
School of Medicine, Osaka, Japan), and Hideo Asada (Department of Dermatology, Nara Medical University, Nara, Japan).

REFERENCES
1. Stevens AM, Johnson FC. A new eruptive fever associated with
stomatitis and ophthalmia. Am J Dis Child 1922;24(6):526533.
2. Bastuji-Garin S, Rzany B, Stern RS, Shear NH, Naldi L,
Roujeau JC. Clinical classification of cases of toxic epidermal
necrolysis, Stevens-Johnson syndrome, and erythema multi-
forme. Arch Dermatol 1993;129(1):9296.
3. Roujeau JC. Stevens-Johnson syndrome and toxic epidermal
necrolysis are severity variants of the same disease which differs
from erythema multiforme. J Dermatol 1997;24(11):726729.
4. Auquier-Dunant A, Mockenhaupt M, Naldi L, Correia O,
Schroder W, Roujeau JC. Correlations between clinical pat-
terns and causes of erythema multiforme majus, Stevens-
Johnson syndrome, and toxic epidermal necrolysis: results of
an international prospective study. Arch Dermatol 2002;
138(8):10191024.
5. Roujeau JC, Stern RS. Severe adverse cutaneous reactions to
drugs. N Engl J Med 1994;331(19):12721285.
6. Yamane Y, Aihara M, Ikezawa Z. Analysis of Stevens-Johnson
syndrome and toxic epidermal necrolysis in Japan from 2000
to 2006. Allergol Int 2007;56(4):419425.
7. Sotozono C, Ueta M, Koizumi N, et al. Diagnosis and treat-
ment of Stevens-Johnson syndrome and toxic epidermal
necrolysis with ocular complications. Ophthalmology 2009;
116(4):685690.
8. Sotozono C, Ang LP, Koizumi N, et al. New grading system for
the evaluation of chronic ocular manifestations in patients
with Stevens-Johnson syndrome. Ophthalmology 2007;114(7):
12941302.
9. Koizumi N, Inatomi T, Suzuki T, Sotozono C, Kinoshita S.
Cultivated corneal epithelial transplantation for ocular surface
reconstruction in acute phase of Stevens-Johnson syndrome.
Arch Ophthalmol 2001;119(2):298300.
10. Koizumi N, Inatomi T, Suzuki T, Sotozono C, Kinoshita S.
Cultivated corneal epithelial stem cell transplantation in
ocular surface disorders. Ophthalmology 2001;108(9):
15691574.
11. Inatomi T, Nakamura T, Koizumi N, Sotozono C, Yokoi N,
Kinoshita S. Midterm results on ocular surface reconstruction
using cultivated autologous oral mucosal epithelial transplan-
tation. Am J Ophthalmol 2006;141(2):267275.
12. Inatomi T, Nakamura T, Kojyo M, Koizumi N, Sotozono C,
Kinoshita S. Ocular surface reconstruction with combination
of cultivated autologous oral mucosal epithelial transplantation
and penetrating keratoplasty. Am J Ophthalmol 2006;142(5):
757764.
13. Sotozono C, Inatomi T, Nakamura T, et al. Visual improve-
ment after cultivated oral mucosal epithelial transplantation.
Ophthalmology 2013;120(1):193200.
14. Sotozono C, Inatomi T, Nakamura T, et al. Cultivated oral
mucosal epithelial transplantation for persistent epithelial

236 AMERICAN JOURNAL OF OPHTHALMOLOGY AUGUST 2015

 defect in severe ocular surface diseases with acute inflamma-
tory activity. Acta Ophthalmol 2014;92(6):e447453.
15. Sotozono C, Yamauchi N, Maeda S, Kinoshita S. Tear
exchangeable limbal rigid contact lens for ocular sequelae
due to Stevens-Johnson syndrome or toxic epidermal necrol-
ysis. Am J Ophthalmol 2014;158(5):983993.
16. Power WJ, Ghoraishi M, Merayo-Lloves J, Neves RA,
Foster CS. Analysis of the acute ophthalmic manifestations
of the erythema multiforme/Stevens-Johnson syndrome/toxic
epidermal necrolysis disease spectrum. Ophthalmology 1995;
102(11):16691676.
17. Paul C, Wolkenstein P, Adle H, et al. Apoptosis as a mech-
anism of keratinocyte death in toxic epidermal necrolysis.
Br J Dermatol 1996;134(4):710714.
18. Araki Y, Sotozono C, Inatomi T, et al. Successful treatment of
Stevens-Johnson syndrome with steroid pulse therapy at disease
onset. Am J Ophthalmol 2009;147(6):10041011, 1011 e1.
19. Yagi T, Sotozono C, Tanaka M, et al. Cytokine storm arising
on the ocular surface in a patient with Stevens-Johnson syn-
drome. Br J Ophthalmol 2011;95(7):10301031.
20. Bastuji-Garin S, Fouchard N, Bertocchi M, Roujeau JC,
Revuz J, Wolkenstein P. SCORTEN: a severity-of-illness
score for toxic epidermal necrolysis. J Invest Dermatol 2000;
115(2):149153.
21. Mockenhaupt M, Viboud C, Dunant A, et al. Stevens-Johnson
syndrome and toxic epidermal necrolysis: assessment of medi-
cation risks with emphasis on recently marketed drugs. The
EuroSCAR-study. J Invest Dermatol 2008;128(1):3544.
22. Schneck J, Fagot JP, Sekula P, Sassolas B, Roujeau JC,
Mockenhaupt M. Effects of treatments on the mortality of
Stevens-Johnson syndrome and toxic epidermal necrolysis:
a retrospective study on patients included in the prospective
EuroSCAR Study. J Am Acad Dermatol 2008;58(1):3340.
23. Lee HY, Dunant A, Sekula P, et al. The role of prior cortico-
steroid use on the clinical course of Stevens-Johnson syndrome
and toxic epidermal necrolysis: a case-control analysis of pa-
tients selected from the multinational EuroSCAR and RegiS-
CAR studies. Br J Dermatol 2012;167(3):555562.
24. Kitami A, Watanabe H, Sueki H, et al. Epidemiological survey
of Stevens-Johnson syndrome and toxic epidermal necrolysis
throughout Japan: supported by the Japanese Research Com-
mittee on Severe Adverse Reactions (J-SCAR) and partially
by Health and Labor Sciences research grants (Research on
Intractable Diseases) from the Ministry of Health, Labor and
Welfare of Japan and the Japanese Dermatological Associa-
tion. Jpn J Dermatol 2011;121(12):24672482.
25. Kaido M, Dogru M, Yamada M, et al. Functional visual acuity in
Stevens-Johnson syndrome. Am J Ophthalmol 2006;142(6):
917922.
26. Kaido M, Yamada M, Sotozono C, et al. The relation between
visual performance and clinical ocular manifestations in
Stevens-Johnson syndrome. Am J Ophthalmol 2012;154(3):
499511.e1.
27. Watanabe R, Watanabe H, Sotozono C, Kokaze A, Iijima M.
Critical factors differentiating erythema multiforme majus
from Stevens-Johnson syndrome (SJS)/toxic epidermal
necrolysis (TEN). Eur J Dermatol 2011;21(6):889894.
VOL. 160, NO. 2 SIMPLE SCORING OF OCULAR SEVERITY AND PREDICTIVE FACTORS IN SJS/TEN
28. Morales ME, Purdue GF, Verity SM, Arnoldo BD,
Blomquist PH. Ophthalmic manifestations of Stevens-
Johnson syndrome and toxic epidermal necrolysis and relation
to SCORTEN. Am J Ophthalmol 2010;150(4):505510.e1.
29. Ueta M, Sotozono C, Inatomi T, Kojima K, Hamuro J,
Kinoshita S. Association of IL4R polymorphisms with
Stevens-Johnson syndrome. J Allergy Clin Immunol 2007;
120(6):14571459.
30. Ueta M, Sotozono C, Inatomi T, et al. Toll-like receptor 3
gene polymorphisms in Japanese patients with Stevens-
Johnson syndrome. Br J Ophthalmol 2007;91(7):962965.
31. Ueta M, Sotozono C, Tokunaga K, Yabe T, Kinoshita S.
Strong association between HLA-A*0206 and Stevens-
Johnson syndrome in the Japanese. Am J Ophthalmol 2007;
143(2):367368.
32. Ueta M, Tokunaga K, Sotozono C, et al. HLA class I and II
gene polymorphisms in Stevens-Johnson syndrome with
ocular complications in Japanese. Mol Vis 2008;14:550555.
33. Ueta M, Sotozono C, Inatomi T, Kojima K, Hamuro J,
Kinoshita S. Association of combined IL-13/IL-4R signaling
pathway gene polymorphism with Stevens-Johnson syndrome
accompanied by ocular surface complications. Invest Ophthal-
mol Vis Sci 2008;49(5):18091813.
34. Ueta M, Sotozono C, Nakano M, et al. Association between
prostaglandin E receptor 3 polymorphisms and Stevens-
Johnson syndrome identified by means of a genome-wide as-
sociation study. J Allergy Clin Immunol 2010;126(6):
12181225.e10.
35. Kaniwa N, Saito Y, Aihara M, et al. HLA-B locus in Japanese
patients with anti-epileptics and allopurinol-related Stevens-
Johnson syndrome and toxic epidermal necrolysis. Pharmaco-
genomics 2008;9(11):16171622.
36. Ueta M, Sotozono C, Yokoi N, Inatomi T, Kinoshita S. Pros-
taglandin E receptor subtype EP3 expression in human
conjunctival epithelium and its changes in various ocular sur-
face disorders. PloS One 2011;6(9):e25209.
37. Ueta M, Tokunaga K, Sotozono C, et al. HLA-A*0206 with
TLR3 polymorphisms exerts more than additive effects in
Stevens-Johnson syndrome with severe ocular surface com-
plications. PloS One 2012;7(8):e43650.
38. Tohkin M, Kaniwa N, Saito Y, et al. A whole-genome
association study of major determinants for allopurinol-
related Stevens-Johnson syndrome and toxic epidermal
necrolysis in Japanese patients. Pharmacogenomics 2013;
13(1):6069.
39. Kaniwa N, Sugiyama E, Saito Y, et al. Specific HLA types are
associated with antiepileptic drug-induced Stevens-Johnson
syndrome and toxic epidermal necrolysis in Japanese subjects.
Pharmacogenomics 2013;14(15):18211831.
40. Isogai H, Miyadera H, Ueta M, et al. In silico risk assessment
of HLA-A*02:06-associated Stevens-Johnson syndrome and
toxic epidermal necrolysis caused by cold medicine ingredi-
ents. J Toxicol 2013;2013:514068.
41. Ueta M, Kaniwa N, Sotozono C, et al. Independent strong as-
sociation of HLA-A*02:06 and HLA-B*44:03 with cold
medicine-related Stevens-Johnson syndrome with severe
mucosal involvement. Sci Rep 2014;4:4862.
237
 Biosketch
Dr. Chie Sotozono graduated from the Kyoto Prefectural University of Medicine, Kyoto, Japan in 1986, and subsequently
completed her residency training at the Department of Ophthalmology of that same prestigious university. Dr. Sotozono
received her Ph.D. from the Kyoto Prefectural University of Medicine at 1995. At present, Dr. Sotozono is an Assistant
Professor in the Department of Ophthalmology at Kyoto Prefectural University of Medicine, and specializes in clinical
research and cornea-related diseases and regenerative medicine.

237.e1 AMERICAN JOURNAL OF OPHTHALMOLOGY AUGUST 2015

 SUPPLEMENTAL TABLE. Systemic Severity Index Score
for Stevens-Johnson Syndrome and Toxic Epidermal
Necrolysis

Evaluated Condition Score

1. Mucous lesions
Ocular lesions
Pseudomembrane formation 1
Ocular surface epithelial defect (Ocular surface 1
erosive lesions)
Bilateral acute keratoconjunctivitis 1
Labial and/or oral lesions
Oral diffuse erosive lesions with bloody scales 1
Labial erosive lesions with bloody scales alone 1
Oral or labial erosive lesions alone 1
Genital involvement 1
2. Body surface area of skin lesions (select 1 from the 3)
>
_30% 3
10%30% 2
<10% 1
_38.0 8 C
3. Fever: > 1
4. Respiratory dysfunction 1
5. Epidermal detachment 1
6. Liver dysfunction (ALT > _ 100 IU/L) 1

ALT alanine aminotransferase.

The summed score > _6 was treated as severe and summed
scores < _5 was treated as moderate. Each of the following condi-
tions is evaluated as severe regardless of the summed score: (1)
pseudomembrane formation and/or ocular surface epithelial
defect, (2) respiratory dysfunction associated with Stevens-
Johnson syndrome/toxic epidermal necrolysis, (3) toxic
epidermal necrolysis extends with diffuse erythema.

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